T-DXd Outscores T-DM1 Across HER2 Copy-Number, PI3K, and HRD Genomic Subsets in DESTINY-Breast03

In this ctDNA biomarker dive from the Phase III DESTINY-Breast03 trial (n≈420), researchers profiled >700 genes at baseline and progression. Despite wide heterogeneity—PIK3CA 48%, TP53 73%, HER2 amplifications detected in only 56% of plasma samples—trastuzumab deruxtecan kept its edge: ORR 77-87% and median PFS 21-37 mo regardless of high vs low vs undetectable HER2 copy number, PI3K-pathway mutation, or HRD/BRCA status. By contrast, trastuzumab emtansine faltered when HER2 copy number or HRD markers were low/positive (ORR 31-50%, mPFS 5-10 mo; HR for PI3K-mut 0.41 vs wild-type). T-DXd’s 22-month PFS gain over T-DM1 held steady across every genomic slice examined.

https://aacrjournals.org/clincancerres/article/31/12_Supplement/PS8-03/753557/Abstract-PS8-03-Exploratory-biomarker-analysis-of